Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2504
| Predicate | Object |
|---|---|
| rdf:type | |
| rdfs:label |
Xeloda (Tablet, Film Coated)
|
| dailymed-instance:dosage |
The recommended dose of XELODA is 1250 mg/madministered orally twice daily (morning and evening; equivalent to 2500 mg/mtotal daily dose) for 2 weeks followed by a 1-week rest period given as 3-week cycles. XELODA tablets should be swallowed with water within 30 minutes after a meal. In combination with docetaxel, the recommended dose of XELODA is 1250 mg/mtwice daily for 2 weeks followed by a 1-week rest period, combined with docetaxel at 75 mg/mas a 1-hour intravenous infusion every 3 weeks. Pre-medication, according to the docetaxel labeling, should be started prior to docetaxel administration for patients receiving the XELODA plus docetaxel combination. Table 17 displays the total daily dose by body surface area and the number of tablets to be taken at each dose. Adjuvant treatment in patients with Dukes' C colon cancer is recommended for a total of 6 months, ie, XELODA 1250 mg/morally twice daily for 2 weeks followed by a 1-week rest period, given as 3-week cycles for a total of 8 cycles (24 weeks).<br/>Dose Management Guidelines: XELODA dosage may need to be individualized to optimize patient management. Patients should be carefully monitored for toxicity and doses of XELODA should be modified as necessary to accommodate individual patient tolerance to treatment . Toxicity due to XELODA administration may be managed by symptomatic treatment, dose interruptions and adjustment of XELODA dose. Once the dose has been reduced it should not be increased at a later time. The dose of phenytoin and the dose of coumarin-derivative anticoagulants may need to be reduced when either drug is administered concomitantly with XELODA . XELODA dose modification scheme as described below (see Table 18 and Table 19) is recommended for the management of adverse events. Dose modification for the use of XELODA as monotherapy is shown in Table 19. Dosage modifications are not recommended for grade 1 events. Therapy with XELODA should be interrupted upon the occurrence of a grade 2 or 3 adverse experience. Once the adverse event has resolved or decreased in intensity to grade 1, then XELODA therapy may be restarted at full dose or as adjusted according to Table 18 and Table 19. If a grade 4 experience occurs, therapy should be discontinued or interrupted until resolved ordecreased to grade 1, and therapy should be restarted at 50% of the original dose. Doses of XELODA omitted for toxicity are not replaced or restored; instead the patient should resume the planned treatment cycles.<br/>Adjustment of Starting Dose in Special Populations:<br/>Hepatic Impairment: In patients with mild to moderate hepatic dysfunction due to liver metastases, no starting dose adjustment is necessary; however, patients should be carefully monitored. Patients with severe hepatic dysfunction have not been studied.<br/>Renal Impairment: No adjustment to the starting dose of XELODA is recommended in patients with mild renal impairment (creatinine clearance = 51 to 80 mL/min [Cockroft and Gault, as shown below]). In patients with moderate renal impairment (baseline creatinine clearance = 30 to 50 mL/min), a dose reduction to 75% of the XELODA starting dose when used as monotherapy or in combination with docetaxel (from 1250 mg/mto 950 mg/mtwice daily) is recommended . Subsequent dose adjustment is recommended as outlined in Table 18 and Table 19 if a patient develops a grade 2 to 4 adverse event . The starting dose adjustment recommendations for patients with moderate renal impairment apply both to XELODA monotherapy and XELODA in combination use with docetaxel. Cockroft and Gault Equation: (140 - age [yrs]) (body wt [kg]) Creatinine clearance for males =��������������������������������������� (72) (serum creatinine [mg/dL]) Creatinine clearance for females = 0.85��male value<br/>Geriatrics: Physicians should exercise caution in monitoring the effects of XELODA in the elderly. Insufficient data are available to provide a dosage recommendation.
|
| dailymed-instance:descripti... |
XELODA (capecitabine) is a fluoropyrimidine carbamate with antineoplastic activity. It is an orally administered systemic prodrug of 5'-deoxy-5-fluorouridine (5'-DFUR) which is converted to 5-fluorouracil. The chemical name for capecitabine is 5'-deoxy-5-fluoro-N-[(pentyloxy) carbonyl]-cytidine and has a molecular weight of 359.35. Capecitabine has the following structural formula: Capecitabine is a white to off-white crystalline powder with an aqueous solubility of 26 mg/mL at 20��C. XELODA is supplied as biconvex, oblong film-coated tablets for oral administration. Each light peach-colored tablet contains 150 mg capecitabine and each peach-colored tablet contains 500 mg capecitabine. The inactive ingredients in XELODA include: anhydrous lactose, croscarmellose sodium, hydroxypropyl methylcellulose, microcrystalline cellulose,magnesium stearate and purified water. The peach or light peach film coating contains hydroxypropyl methylcellulose, talc, titanium dioxide, and synthetic yellow and red iron oxides.
|
| dailymed-instance:clinicalP... |
XELODA is relatively non-cytotoxic in vitro. This drug is enzymatically converted to 5-fluorouracil (5-FU) in vivo.<br/>Bioactivation: Capecitabine is readily absorbed from the gastrointestinal tract. In the liver, a 60 kDa carboxylesterase hydrolyzes much of the compound to 5'-deoxy-5-fluorocytidine (5'-DFCR). Cytidine deaminase, an enzyme found in most tissues, including tumors, subsequently converts 5'-DFCR to 5'-deoxy-5-fluorouridine (5'-DFUR). The enzyme, thymidine phosphorylase (dThdPase),then hydrolyzes 5'-DFUR to the active drug 5-FU. Many tissues throughout the body express thymidine phosphorylase. Some human carcinomas express this enzyme in higher concentrations than surrounding normal tissues. Metabolic Pathway of capecitabine to 5-FU<br/>Mechanism of Action: Both normal and tumor cells metabolize 5-FU to 5-fluoro-2'-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). These metabolites cause cell injury by two different mechanisms. First, FdUMP and the folate cofactor, N-methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form a covalently bound ternary complex. This binding inhibits the formation of thymidylate from 2'-deoxyuridylate. Thymidylate is the necessary precursor of thymidine triphosphate, which is essential for the synthesis of DNA, so that a deficiency of this compound can inhibit cell division. Second, nuclear transcriptional enzymes can mistakenly incorporate FUTP in place of uridine triphosphate (UTP) during the synthesis of RNA. This metabolic error can interfere with RNA processing and protein synthesis.<br/>Pharmacokinetics in Colorectal Tumors and Adjacent Healthy Tissue: Following oral administration of XELODA 7 days before surgery in patients with colorectal cancer, the median ratio of 5-FU concentration in colorectal tumors to adjacent tissues was 2.9 (range from 0.9 to 8.0). These ratios have not been evaluated in breast cancer patients or compared to 5-FU infusion.<br/>Human Pharmacokinetics: The pharmacokinetics of XELODA and its metabolites have been evaluated in about 200 cancer patients over a dosage range of 500 to 3500 mg/m/day. Over this range, the pharmacokinetics of XELODA and its metabolite, 5'-DFCR were dose proportional and did not change over time. The increases in the AUCs of 5'-DFUR and 5-FU, however, were greater than proportional to the increase in dose and the AUC of 5-FU was 34% higher on day 14 than on day 1. The elimination half-life of both parent capecitabine and 5-FU was about��of an hour. The inter-patient variability in the Cand AUC of 5-FU was greater than 85%. Following oral administration of 825 mg/mcapecitabine twice daily for 14 days, Japanese patients (n=18) had about 36% lower Cand 24% lower AUC for capecitabine than the Caucasian patients (n=22). Japanese patients had also about 25% lower Cand 34% lower AUC for FBAL than the Caucasian patients. The clinical significance of these differences is unknown. No significant differences occurred in the exposure to other metabolites (5'-DFCR, 5'-DFUR, and 5-FU).<br/>Absorption, Distribution, Metabolism and Excretion: Capecitabine reached peak blood levels in about 1.5 hours (T) with peak 5-FU levels occurring slightly later, at 2 hours. Food reduced both the rate and extent of absorption of capecitabine with mean Cand AUCdecreased by 60% and 35%, respectively. The Cand AUCof 5-FU were also reduced by food by 43% and 21%, respectively. Food delayed Tof both parent and 5-FU by 1.5 hours . Plasma protein binding of capecitabine and its metabolites is less than 60% and is not concentration-dependent. Capecitabine was primarily bound to human albumin (approximately 35%). Capecitabine is extensively metabolized enzymatically to 5-FU. The enzyme dihydropyrimidine dehydrogenase hydrogenates 5-FU, the product of capecitabine metabolism, to the much less toxic 5-fluoro-5, 6-dihydro-fluorouracil (FUH). Dihydropyrimidinase cleaves the pyrimidine ring to yield 5-fluoro-ureido-propionic acid (FUPA). Finally,��-ureido-propionase cleaves FUPA to��-fluoro-��-alanine (FBAL) which is cleared in the urine. Capecitabine and its metabolites are predominantly excreted in urine; 95.5% of administered capecitabine dose is recovered in urine. Fecal excretion is minimal (2.6%). The major metabolite excreted in urine is FBAL which represents 57% of the administered dose. About 3% of the administered dose is excreted in urine as unchanged drug. A clinical phase 1 study evaluating the effect of XELODA on the pharmacokinetics of docetaxel (Taxotere') and the effect of docetaxel on the pharmacokinetics of XELODA was conducted in 26 patients with solid tumors. XELODA was found to have no effect on the pharmacokinetics of docetaxel (Cand AUC) and docetaxel has no effect on the pharmacokinetics of capecitabine and the 5-FU precursor 5'-DFUR.<br/>Special Populations: A population analysis of pooled data from the two large controlled studies in patients with metastatic colorectal cancer (n=505) who were administered XELODA at 1250 mg/mtwice a day indicated that gender (202 females and 303 males) and race (455 white/Caucasian patients, 22 black patients, and 28 patients of other race) have no influence on the pharmacokinetics of 5'-DFUR, 5-FU and FBAL. Age has no significant influence on the pharmacokinetics of 5'-DFUR and 5-FU over the range of 27 to 86 years. A 20% increase in age results in a 15% increase in AUC of FBAL .<br/>Hepatic Insufficiency: XELODA has been evaluated in 13 patients with mild to moderate hepatic dysfunction due to liver metastases defined by a composite score including bilirubin, AST/ALT and alkaline phosphatase following a single 1255 mg/mdose of XELODA. Both AUCand Cof capecitabine increased by 60% in patients with hepatic dysfunction compared to patients with normal hepatic function (n=14). The AUCand Cof 5-FU were not affected. In patients with mild to moderate hepatic dysfunction due to liver metastases, caution should be exercised when XELODA is administered. The effect of severe hepatic dysfunction on XELODA is not known .<br/>Renal Insufficiency: Following oral administration of 1250 mg/mcapecitabine twice a day to cancer patients with varying degrees of renal impairment, patients with moderate (creatinine clearance = 30 to 50 mL/min) and severe (creatinine clearance<30 mL/min) renal impairment showed 85% and 258% higher systemic exposure to FBAL on day 1 compared to normal renal function patients (creatinine clearance>80 mL/min). Systemic exposure to 5'-DFUR was 42% and 71% greater in moderately and severely renal impaired patients, respectively, than in normal patients. Systemic exposure to capecitabine was about 25% greater in both moderately and severely renal impaired patients .<br/>Drug-Drug Interactions:<br/>Anticoagulants: In four patients with cancer, chronic administration of capecitabine (1250 mg/mbid) with a single 20 mg dose of warfarin increased the mean AUC of S-warfarin by 57% and decreased its clearance by 37%. Baseline corrected AUC of INR in these 4 patients increased by 2.8-fold, and the maximum observed mean INR value was increased by 91% .<br/>Drugs Metabolized by Cytochrome P450 Enzymes: In vitro enzymatic studies with human liver microsomes indicated that capecitabine and its metabolites (5'-DFUR, 5'-DFCR, 5-FU, and FBAL) had no inhibitory effects on substrates of cytochrome P450 for the major isoenzymes such as 1A2, 2A6, 3A4, 2C9, 2C19, 2D6, and 2E1.<br/>Antacid: When Maalox' (20 mL), an aluminum hydroxide- and magnesium hydroxide-containing antacid, was administered immediately after XELODA (1250 mg/m, n=12 cancer patients), AUC and Cincreased by 16% and 35%, respectively, for capecitabine and by 18% and 22%, respectively, for 5'-DFCR. No effect was observed on the other three major metabolites (5'-DFUR, 5-FU, FBAL) of XELODA. XELODA has a low potential for pharmacokinetic interactions related to plasma protein binding.
|
| dailymed-instance:activeIng... | |
| dailymed-instance:supply |
XELODA is supplied as biconvex, oblong film-coated tablets, available in bottles as follows: 150 mg color: light peachengraving: XELODA on one side, 150 on the other150 mg tablets are packaged in bottles of 60 (NDC 0004-1100-20). 500 mg color: peachengraving: XELODA on one side, 500 on the other500 mg tablets are packaged in bottles of 120 (NDC 0004-1101-50).<br/>Storage Conditions: Store at 25��C (77��F); excursions permitted to 15��to 30��C (59��to 86��F). [See USP Controlled Room Temperature]. KEEP TIGHTLY CLOSED. Maalox is a registered trademark of Novartis Consumer Health. Taxotere is a registered trademark of Aventis Pharma S.A. For full Taxotere prescribing information, please refer to Taxotere Package Insert.
|
| dailymed-instance:genericDr... | |
| dailymed-instance:boxedWarn... |
WARNING: XELODA Warfarin Interaction: Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored frequently in order to adjust the anticoagulant dose accordingly. A clinically important XELODA-Warfarin drug interaction was demonstrated in a clinical pharmacology trial .Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking XELODA concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. Postmarketing reports have shown clinically significant increases in prothrombin time (PT) and INR in patients who were stabilized on anticoagulants at the time XELODA was introduced. These events occurred within several days and up to several months after initiating XELODA therapy and, in a few cases, within 1month after stopping XELODA. These events occurred in patients with and without liver metastases. Age greater than 60 and a diagnosis of cancer independently predispose patients to an increased risk of coagulopathy.
|
| dailymed-instance:activeMoi... | |
| dailymed-instance:inactiveI... |
dailymed-ingredient:anhydrous_lactose,
dailymed-ingredient:croscarmellose_sodium,
dailymed-ingredient:hydroxypropyl_methylcellulose,
dailymed-ingredient:magnesium_stearate,
dailymed-ingredient:microcrystalline_cellulose,
dailymed-ingredient:synthetic_yellow_and_red_iron_oxides,
dailymed-ingredient:talc,
dailymed-ingredient:titanium_dioxide,
dailymed-ingredient:water
|
| dailymed-instance:possibleD... | |
| dailymed-instance:overdosag... |
The manifestations of acute overdose would include nausea, vomiting, diarrhea, gastrointestinal irritation and bleeding, and bone marrow depression. Medical management of overdose should include customary supportive medical interventions aimed at correcting the presenting clinical manifestations. Although no clinical experience using dialysis as a treatment for XELODA overdose has been reported, dialysis may be of benefit in reducing circulating concentrations of 5'-DFUR, a low���molecular-weight metabolite of the parent compound. Single doses of XELODA were not lethal to mice, rats, and monkeys at doses up to 2000 mg/kg (2.4, 4.8, and 9.6 times the recommended human daily dose on a mg/mbasis).
|
| dailymed-instance:genericMe... |
capecitabine
|
| dailymed-instance:fullName |
Xeloda (Tablet, Film Coated)
|
| dailymed-instance:adverseRe... |
Adjuvant Colon Cancer: Table 11 shows the adverse events occurring in���5% of patients from one phase 3 trial in patients with Dukes' C colon cancer who received at least one dose of study medication and had at least one safety assessment. A total of 995 patients were treated with 1250 mg/mtwice a day of XELODA administered for 2 weeks followed by a 1-week rest period, and 974 patients were administered 5-FU and leucovorin (20 mg/mleucovorin IV followed by 425 mg/mIV bolus 5-FU, on days 1-5, every 28 days). The median duration of treatment was 164 days for capecitabine-treated patients and 145 days for 5-FU/LV-treated patients. A total of 112 (11%) and 73 (7%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse events. A total of 18 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 8 (0.8%) patients randomized to XELODA and 10 (1.0%) randomized to 5-FU/LV. Table 12 shows grade 3/4 laboratory abnormalities occurring in���1% of patients from one phase 3 trial in patients with Dukes' C colon cancer who received at least one dose of study medication and had at least one safety assessment.<br/>Metastatic Colorectal Cancer: Table 13 shows the adverse events occurring in���5% of patients from pooling the two phase 3 trials in first line metastatic colorectal cancer. A total of 596 patients with metastatic colorectal cancer were treated with 1250 mg/mtwice a day of XELODA administered for 2 weeks followed by a 1-week rest period, and 593 patients were administered 5-FU and leucovorin in the Mayo regimen (20 mg/mleucovorin IV followed by 425 mg/mIV bolus 5-FU, on days 1-5, every 28 days). In the pooled colorectal database the median duration of treatment was 139 days for capecitabine-treated patients and 140 days for 5-FU/LV-treated patients. A total of 78 (13%) and 63 (11%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse events/intercurrent illness. A total of 82 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 50 (8.4%) patients randomized to XELODA and 32 (5.4%) randomized to 5-FU/LV.<br/>Breast Cancer Combination: The following data are shown for the combination study with XELODA and docetaxel in patients with metastatic breast cancer in Table 14 and Table 15. In the XELODA and docetaxel combination arm the treatment was XELODA administered orally 1250 mg/mtwice daily as intermittent therapy (2 weeks of treatment followed by 1 week without treatment) for at least 6 weeks and docetaxel administered as a 1-hour intravenous infusion at a dose of 75 mg/mon the first day of each 3-week cycle for at least 6 weeks. In the monotherapy arm docetaxel was administered as a 1-hour intravenous infusion at a dose of 100 mg/mon the first day of each 3-week cycle for at least 6 weeks. The mean duration of treatment was 129 days in the combination arm and 98 days in the monotherapy arm. A total of 66 patients (26%) in the combination arm and 49 (19%) in the monotherapy arm withdrew from the study because of adverse events. The percentage of patients requiring dose reductions due to adverse events was 65% in the combination arm and 36% in the monotherapy arm. The percentage of patients requiring treatment interruptions due to adverse events in the combination arm was 79%. Treatment interruptions were part of the dose modification scheme for the combination therapy arm but not for the docetaxel monotherapy-treated patients.<br/>Breast Cancer XELODA Monotherapy: The following data are shown for the study in stage IV breast cancer patients who received a dose of 1250 mg/madministered twice daily for 2 weeks followed by a 1-week rest period. The mean duration of treatment was 114 days. A total of 13 out of 162 patients (8%) discontinued treatment because of adverse events/intercurrent illness.<br/>XELODA and Docetaxel in Combination: Shown below by body system are the clinically relevant adverse events in<5% of patients in the overall clinical trial safety database of 251 patients (Study Details) reported as related to the administration of XELODA in combination with docetaxel and that were clinically at least remotely relevant. In parentheses is the incidence of grade 3 and 4 occurrences of each adverse event. It is anticipated that the same types of adverse events observed in the XELODA monotherapy studies may be observed in patients treated with the combination of XELODA plus docetaxel. Gastrointestinal: ileus (0.39), necrotizing enterocolitis (0.39), esophageal ulcer (0.39), hemorrhagic diarrhea (0.80) Neurological: ataxia (0.39), syncope (1.20), taste loss (0.80), polyneuropathy (0.39), migraine (0.39) Cardiac: supraventricular tachycardia (0.39) Infection: neutropenic sepsis (2.39), sepsis (0.39), bronchopneumonia (0.39) Blood and Lymphatic: agranulocytosis (0.39), prothrombin decreased (0.39) Vascular: hypotension (1.20), venous phlebitis and thrombophlebitis (0.39), postural hypotension (0.80) Renal: renal failure (0.39) Hepatobiliary: jaundice (0.39), abnormal liver function tests (0.39), hepatic failure (0.39), hepatic coma (0.39), hepatotoxicity (0.39) Immune System: hypersensitivity (1.20)<br/>XELODA Monotherapy Metastatic Breast and Colorectal Cancer: Shown below by body system are the clinically relevant adverse events in<5% of patients in the overall clinical trial safety database of 875 patients (phase 3 colorectal studies���596 patients, phase 2 colorectal study���34 patients, phase 2 breast cancer studies���245 patients) reported as related to the administration of XELODA and that were clinically at least remotely relevant. In parentheses is the incidence of grade 3 or 4 occurrences of each adverse event. Gastrointestinal: abdominal distension, dysphagia, proctalgia, ascites (0.1), gastric ulcer (0.1), ileus (0.3), toxic dilation of intestine, gastroenteritis (0.1) Skin and Subcutaneous: nail disorder (0.1), sweating increased (0.1), photosensitivity reaction (0.1), skin ulceration, pruritus, radiation recall syndrome (0.2) General: chest pain (0.2), influenza-like illness, hot flushes, pain (0.1), hoarseness, irritability, difficulty in walking, thirst, chest mass, collapse, fibrosis (0.1), hemorrhage, edema, sedation Neurological: insomnia, ataxia (0.5), tremor, dysphasia, encephalopathy (0.1), abnormal coordination, dysarthria, loss of consciousness (0.2), impaired balance Metabolism: increased weight, cachexia (0.4), hypertriglyceridemia (0.1), hypokalemia, hypomagnesemia Eye: conjunctivitis Respiratory: cough (0.1), epistaxis (0.1), asthma (0.2), hemoptysis, respiratory distress (0.1), dyspnea Cardiac: tachycardia (0.1), bradycardia, atrial fibrillation, ventricular extrasystoles, extrasystoles, myocarditis (0.1), pericardial effusion Infections: laryngitis (1.0), bronchitis (0.2), pneumonia (0.2), bronchopneumonia (0.2), keratoconjunctivitis, sepsis (0.3), fungal infections (including candidiasis) (0.2) Musculoskeletal: myalgia, bone pain (0.1), arthritis (0.1), muscle weakness Blood and Lymphatic: leukopenia (0.2), coagulation disorder (0.1), bone marrow depression (0.1), idiopathic thrombocytopenia purpura (1.0), pancytopenia (0.1) Vascular: hypotension (0.2), hypertension (0.1), lymphoedema (0.1), pulmonary embolism (0.2), cerebrovascular accident (0.1) Psychiatric: depression, confusion (0.1) Renal: renal impairment (0.6) Ear: vertigo Hepatobiliary: hepatic fibrosis (0.1), hepatitis (0.1), cholestatic hepatitis (0.1), abnormal liver function tests Immune System: drug hypersensitivity (0.1) Postmarketing: hepatic failure, lacrimal duct stenosis
|
| dailymed-instance:indicatio... |
Colorectal Cancer:<br/>Breast Cancer:
|
| dailymed-instance:represent... | |
| dailymed-instance:routeOfAd... | |
| dailymed-instance:name |
Xeloda
|